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PPAR-gamma is expressed and NF-kB pathway is activated and correlates positively with COX-2 expression in stromal myofibroblasts surrounding colon adenocarcinomas

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Purpose: Accumulated evidence indicates that carcinogenesis is closely associated with the transformation of normal stroma into a ‘reactive’ stromal phenotype. The present study investigated the role of PPARγ, COX-2 and p-IkB-α—important molecular targets of colon cancer chemoprevention—in this stromal remodeling by evaluating and comparing the expression of these factors in stromal myofibroblasts, macrophages and endothelial cells that surround normal colonic mucosa and colon cancer. Methods: Immunohistochemical methodology was employed on archived paraffin-embedded sections prepared from tumors and adjacent normal colon from 45 patients with colon adenocarcinomas. Double immunostaining with the universal marker for myofibroblasts (alpha-smooth muscle actin/α-SMA) as second primary antibody was also performed. Results: Stromal macrophages and endothelial cells expressed these factors both in normal colonic mucosa and colon cancer. By contrast, stromal myofibroblasts expressed PPARγ, COX-2 and p-IkB-α only in colon adenocarcinomas (77.7%, 100% and 100% of cases, respectively) and not in normal colon. COX-2 and p-IkB-α expressions were strongly correlated in these cells (P<0.001). PPARγ, COX-2 and p-IkB-α expression did not correlate with the stage or differentiation of the adenocarcinomas. Conclusions: NF-kB pathway is activated and COX-2 expression is upregulated in stromal myofibroblasts surrounding colon adenocarcinomas compared to normal colon. Induction of COX-2 expression is primarily induced by NF-kB. NSAIDs, selective COX-2 inhibitors and PPARγ ligands may exert their chemoprophylactic properties through direct actions on these cells.

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  1. Adegboyega PA, Ololade O, Saada J, Mifflin R, Di Mari JF, Powell DW (2004) Subepithelial myofibroblasts express cyclooxygenase-2 in colorectal tubular adenomas. Clin Cancer Res 10:5870–5879

  2. Baeuerle PA, Baltimore D (1996) NF-kappa B: ten years after. Cell 87:13–20

  3. Bamba H, Ota S, Kato A, Adachi A, Itoyama S, Matsuzaki F (1999) High expression of cyclooxygenase-2 in macrophages of human colonic adenoma. Int J Cancer 83:470–475

  4. Bosman FT, de Bruine A, Flohil C, van der Wurff A, ten Kate J, Dinjens WW (1993) Epithelial-stromal interactions in colon cancer. Int J Dev Biol 37:203–211

  5. Chung LW, Hsieh CL, Law A, Sung SY, Gardner TA, Egawa M, Matsubara S, Zhau HE (2003) New targets for therapy in prostate cancer: modulation of stromal-epithelial interactions. Urology 62:44–54

  6. Fosslien E (2001) Review: molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis. Ann Clin Lab Sci 31:325–348

  7. Gupta RA, Dubois RN (2001) Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer 1:11–21

  8. Haslam SZ, Woodward TL (2003) Host microenvironment in breast cancer development: epithelial-cell-stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland. Breast Cancer Res 5:208–215

  9. Kojima M, Morisaki T, Izuhara K, Uchiyama A, Matsunari Y, Katano M, Tanaka M (2000) Lipopolysaccharide increases cyclo-oxygenase-2 expression in a colon carcinoma cell line through nuclear factor-kappa B activation. Oncogene 19:1225–1231

  10. Kopp E, Ghosh S (1994) Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 265:956–959

  11. Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O, Takahashi T, Tanabe T (1994) Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. Eur J Biochem 221:889–897

  12. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA (1997) Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem 272:3406–3410

  13. Lu T, Burdelya LG, Swiatkowski SM, A.D. Boiko AD, Howe PH, Stark GR, Gudkov AV (2004) Secreted transforming growth factor beta2 activates NF-kappaB, blocks apoptosis, and is essential for the survival of some tumor cells. Proc Natl Acad Sci U S A 101:7112–7117

  14. Majima M, Amano H, Hayashi I (2003) Prostanoid receptor signaling relevant to tumor growth and angiogenesis. Trends Pharmacol Sci 24:524–529

  15. Mansen A, Guardiola-Diaz H, Rafter J, Branting C, Gustafsson JA (1996) Expression of the peroxisome proliferator-activated receptor (PPAR) in the mouse colonic mucosa. Biochem Biophys Res Commun 222:844–851

  16. Mifflin RC, Saada JI, Di Mari JF, Adegboyega PA, Valentich JD, Powell DW (2002) Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction. Am J Physiol Cell Physiol 282:824–834

  17. Otte JM, Rosenberg IM, Podolsky DK (2003) Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology 124:1866–1878

  18. Panigrahy D, Singer S, Shen LQ, Butterfield CE, Freedman DA, Chen EJ, Moses MA, Kilroy S, Duensing S, Fletcher C, Fletcher JA, Hlatky L, Hahnfeldt P, Folkman J, Kaipainen A (2002) PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J Clin Invest 110:923–32

  19. Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB (1999) Myofibroblasts. I. Paracrine cells important in health and disease. Am J Physiol 277:1–9

  20. Rayet B, Gelinas C (1999) Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18:6938–6947

  21. Ricote M, Huang JT, Welch JS, Glass CK (1999) The peroxisome proliferator-activated receptor(PPARgamma) as a regulator of monocyte/macrophage function. J Leukoc Biol 66:733–739

  22. Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher C, Spiegelman BM (1998) Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med 4:1046–1052

  23. Shattuck-Brandt RL, Varilek GW, Radhika A, Yang F, Washington MK, DuBois RN (2000) Cyclooxygenase 2 expression is increased in the stroma of colon carcinomas from IL-10(-/-) mice. Gastroenterology 118:337–345

  24. Straus DS, Pascual G, Li M, Welch JS, Ricote M, Hsiang CH, Sengchanthalangsy LL, Ghosh G (2000) 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Proc Natl Acad Sci U S A 97:4844–4849

  25. Subbaramaiah K, Lin DT, Hart JC, Dannenberg AJ (2001) Peroxisome proliferator-activated receptor gamma ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein/p300. J Biol Chem 276:12440–12448

  26. Tanabe T, Tohnai N (2002) Cyclooxygenase isozymes and their gene structures and expression. Prostaglandins Other Lipid Mediat 68–69:95–114

  27. Tlsty TD, Hein PW (2001) Know thy neighbor: stromal cells can contribute oncogenic signals. Curr Opin Genet Dev 11:54–59

  28. Verrier E, Wang L, Wadham C, Albanese N, Hahn C, Gamble JR, Chatterjee VK, Vadas MA, Xia P (2004) PPARgamma agonists ameliorate endothelial cell activation via inhibition of diacylglycerol-protein kinase C signaling pathway: role of diacylglycerol kinase. Circ Res 94:1515–1522

  29. Yin MJ, Yamamoto Y, Gaynor RB (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 396:77–80

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We thank H. Nikolopoulou, N. Mpeka and F. Chrysanthopoulos, technicians at the Pathology Department of Aeghion General Hospital for their help and enthusiastic work.

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Correspondence to Athanasios G. Papavassiliou.

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G. P. Vandoros and P. A. Konstantinopoulos contributed equally to this work.

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Vandoros, G.P., Konstantinopoulos, P.A., Sotiropoulou-Bonikou, G. et al. PPAR-gamma is expressed and NF-kB pathway is activated and correlates positively with COX-2 expression in stromal myofibroblasts surrounding colon adenocarcinomas. J Cancer Res Clin Oncol 132, 76–84 (2006).

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  • Peroxisome proliferator-activated receptor gamma
  • Nuclear factor kB
  • Cyclooxygenase-2
  • Myofibroblasts
  • Colon cancer